Periodontal disease is an inflammatory infection that affects 10-15% of the adult population. The pathogen P. gingivalis (Pg) is implicated in disease activation. The chronicity of periodontitis suggests that it may act as a constant, low-grade delivery system of microorganisms and cytokines that influence diseases at distant sites. Clinical studies suggest an association between periodontal disease and other illnesses, such as rheumatoid arthritis (RA). However, the bi-directional disease interaction impedes the clarification of a mechanism linking both diseases. RA is an autoimmune disease that affects 1.3 million U.S. adults. RA is a multi-factorial disease that leads to inflammation and destruction of the joints. Strong evidence suggests that T helper type 17 (Th17) cells play an important role in RA development. The cytokine IL-17 and Th17-inducers IL-1 and IL- 6 are also shown to play an important role in periodontal disease development. Because the control of the cytokine microenvironment influences Th cell activation, we hypothesize that a chronic periodontal infection leads to a shift in cytokine expression and contributes to the development and/or progression of arthritic bone destruction via Th17 cells. This research and training program proposes two aims:
Specific Aim 1 : Compare the systemic cellular acquired immunological response of different strains of P. gingivalis using a murine chronic periodontitis model.
The aim of this approach is to identify whether the chronic periodontal infection of different strains of Pg leads to distinct systemic immunological responses. Mice will be induced for periodontal disease by oral gavage with the following virulent Pg strains A7A1-28, W83, and W50. The acquired immunological response will be evaluated by serum cytokine expression and splenocyte analysis after periodontal disease induction. Based on the results, the Pg strains most relevant for influencing the Th17 immune response and initiating bone loss will be determined and utilized in specific aim 2.
Specific Aim 2 : Determine the acquired immunological effect of chronic periodontal disease during experimental RA development in mice. Mice will undergo induction of periodontal disease followed by collagen-induced arthritis. In vitro studies utilizing dendritic cells and T cells will provide a mechanistic approach for understanding alterations in T cell activation caused by Pg that may affect arthritis development. Serum cytokine and splenocyte analyses will identify changes in T cell activation and the acquisition of effector functions. These studies will provide an excellent training environment for research, involving experts in the fields of periodontology, pathology and immunology. The goal of this proposal is to better understand the immunologic mechanism(s) by which an oral infection could act as an environmental co-factor and influence arthritis.

Public Health Relevance

Clinical studies demonstrate the existence of an association between periodontal disease and rheumatoid arthritic patients. However, the bi-directional influence of one disease on the other impedes the clarification of a mechanism linking both diseases. Strong evidence indicates that T helper type 17 cells drive both diseases, suggesting that the immune system is an important link between periodontitis and rheumatoid arthritis. The proposed research will help investigate the direct influence of periodontal disease in arthritis development. A mouse model will be induced for chronic periodontitis and arthritis for further exploration of the systemic acquired immune response. Identification of potential pathogen-host response modifiers that affect these two chronic, disabling diseases may advance understanding of disease pathogenesis and potential treatment approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DE021934-02
Application #
8331699
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2011-09-01
Project End
2013-04-30
Budget Start
2012-09-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$46,595
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Padial-Molina, Miguel; Volk, Sarah L; Rodriguez, Juan C et al. (2013) Tumor necrosis factor-ýý and Porphyromonas gingivalis lipopolysaccharides decrease periostin in human periodontal ligament fibroblasts. J Periodontol 84:694-703